Protein kinases mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H2O2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Thus, selective kinase and phosphatase inhibitors have emerged as important drug targets, and inhibition of kinase phosphorylation activity is one of the most promising strategies for chemotherapy. Multiple small molecule kinase inhibitor drugs are already approved: Gleevec, which inhibits Abl, and Iressa and Tarceva, which both inhibit EGFR, Sorafenib (Nexavar, BAY 43-9006) which inhibits Raf, Dasatinib (BMS-354825) and Nilotinib (AMN-107, Tasigna) which also inhibits Abl, Lapatinib which also inhibits EGFR, Temsirolimus (Torisel, CCI-779) which targets the mTOR pathway, Sunitinib (Stuten, SU11248) which inhibits several targets including VGFR as well as specific antibodies inactivating kinase receptors: Herceptin and Avastin

Some resorcylic acid macrolides had been known as kinase or phosphatase inhibitors (U.S. Pat. Nos. 5,674,892; 5,728,726; 5,731,343; and 5,795,910; all of which are hereby incorporated by reference in their entirety), or to inhibit other enzymes (U.S. Pat. No. 5,710,174, which is hereby incorporated by reference in its entirety, discloses inhibition of FXIIIa catalysis of fibrin cross-linking). Resorcylic acid macrolides were also employed for other medical indications (U.S. Pat. Nos. 3,453,367; 3,965,275; 4,035,504; 4,670,249; 4,778,821; 4,902,711; and 6,635,671; all incorporated by reference in their entirety).
Radicicol and the pochonins are resorcylic acid lactone natural products, and intermediates for synthesizing some of their analogues may be obtained by fermentation. However, relying only upon those natural products or their fermentation derivatives severely limits the range of compounds. Thus, a number of novel resorcylic acid macrolides have been synthesized. Many of these are zearalane and related compounds in which the macrocyclic ring contains no carbon-carbon double bond other than between carbons of the phenyl ring. (U.S. Pat. Nos. 3,373,038; 3,586,701; 3,621,036; 3,631,179; 3,687,982; 3,704,249; 3,751,431; 3,764,614; 3,810,918; 3,836,544; 3,852,307; 3,860,616; 3,901,921; 3,901,922; 3,903,115; 3,957,825; 4,042,602; 4,751,239; 4,849,447; and U.S. Publication No. 2005-0256183; all of which are incorporated herein by reference). Syntheses have also been reported for resorcylic acid macrolides characterized by one double bond between ring carbons outside the phenyl ring. (U.S. Pat. Nos. 3,196,019; 3,551,454; 3,758,511; 3,887,583; 3,925,423; 3,954,805; and 4,088,658; all of which are incorporated herein by reference). Most of those are 14-member macrocycles, but syntheses have also been reported for the 12-member macrocycle analogues. (U.S. Pat. Nos. 5,710,174; 6,617,348; and U.S. Publication No. 2004-0063778 and PCT Publication No. WO 02/48135; all of which are incorporated by reference in their entirety).
Syntheses have also been reported for radicicol-related compounds having two non-aromatic double bonds and either a halide or a 1,2-oxo group (i.e., an epoxide) on the macrocyclic ring. (U.S. Pat. Nos. 4,228,079; 5,597,846; 5,650,430; 5,977,165; 7,115,651; and Japanese Publication Nos. JP 6-279279A, JP 6-298764A, JP 9-202781A, JP 10-265381A2; and JP 2000-236984). Syntheses of oximes of radicicol-related compounds are disclosed in U.S. Pat. Nos. 5,977,165; 6,239,168; 6,316,491; 6,635,662; 2001-0027208; 2004-0053990; Japanese Publication No. JP 2003-113183A2; and PCT Publication No. WO 99/55689. Synthesis of cyclopropa-analogues of radicicol is disclosed in U.S. Pat. No. 7,115,651 and PCT Publication No. WO 05/061481. Syntheses of some other resorcylic acid macrolide analogues are disclosed in U.S. Publication No. 2006-0247448 and in PCT Publication No. WO 02/48135. Radicicol as well as Pochonins A and C have also been synthesized (S. Barluenga et al., Angew. Chemie, 43(26):3467-3470 (2004); S. Barluenga et al., Chemistry—A European Journal, 11(17):4935-4952 (Aug. 19, 2005); E. Moulin et al., et al., Organic Letters, 7(25):5637-5639 (Dec. 8, 2005).
Radicicol A (F87-25909.04, 1) shown below belongs to the family of resorcylic acid lactones (RAL) and was first reported by researchers from Sandoz who identified this fungal metabolite from a screen for IL1β inhibition (see published European Application No. EP 0606044 A1, which is incorporated herein by reference in its entirety, and N. Winssinger, S. Barluenga, Chem Commit (Camb) 2007, 22; T. Kastelic, J. Schnyder, A. Leutwiler, R. Traber, B. Streit, H. Niggli, A. Mackenzie, D. Cheneval, Cytokine 1996, 8, 751). While it was observed that this compound accelerated the degradation of specific mRNA sequences including IL1βs, its precise molecular target was not identified (D. Cheneval, P. Ramage, T. Kastelic, T. Szelestenyi, H. Niggli, R. Hemmig, M. Bachmann, A. Mackenzie, Journal of Biological Chemistry 1998, 273, 17846). Subsequently, two other related resorcylic acid lactones containing a cis-enone, compounds 3 and 5 below, were reported to be potent irreversible yet selective kinase inhibitors (J. Ninomiya-Tsuji, T. Kajino, K. Ono, T. Ohtomo, M. Matsumoto, M. Shiina, M. Mihara, M. Tsuchiya, K. Matsumoto, Journal of Biological Chemistry 2003, 278, 18485; A. Zhao, S. H. Lee, M. Mojena, R. G. Jenkins, D. R. Patrick, H. E. Huber, M. A. Goetz, O. D. Hensens, D. L. Zink, D. Vilella, A. W. Dombrowski, R. B. Lingham, L. Huang, Journal of Antibiotics 1999, 52, 1086). More recently, Santi and co-workers showed that hypothemycin, which also bears the cis-enone moiety, covalently inactivates ERK2 by reacting with a cysteine residue positioned in the active site, Cys166 (A. Schirmer, J. Kennedy, S. Murli, R. Reid, D. V. Santi, Proc Natl Acad Sci USA 2006, 103, 4234).

Published Japanese Patent Application No. JP 08040893 A discloses macrocycles containing a cis-enone group which are related to radicicol A as useful inhibitors of interleukin-1 (IL-1). The compounds are disclosed to be useful for the treatment of diseases caused by the overproduction of IL-1. Published U.S. Patent Application Nos. US2004/0224936 and 2006/0247448 and published International Application No. WO 03/076424, all which are hereby incorporated by reference in their entirety, describe analogues of radicicol A, which are potent kinase inhibitors and are disclosed to be useful in treating kinase-mediated diseases. Published International Patent Applications No. WO 02/48135, WO 02/48135, WO 2006/036941 and WO 02/48135 and British Patent Application No. GB 2323845 A, all incorporated herein by reference, disclose compounds and compositions related to radicicol A, which are disclosed to be kinase inhibitors.
Interest in the RALs stems from the observation that a significant fraction of the family of natural products has been shown to inhibit kinases and ATPases. Despite the lack of obvious similarities between the RALs and ATPases, these compounds have been shown to bind to the ATP-binding pocket of kinases and ATPase.
Despite the progress described above, chemical biologists continue to suffer from a limited ability to knock out specific kinase activity in order to deconvolute the role of specific kinases within complex signaling networks. Small molecules that can permeate cells have promise for solving this problem. And it has become increasingly apparent that the biological function of kinases is often regulated by their conformation, which is in turn dictated by their phosphorylation level and by intra- and inter-molecular associations. Small molecule inhibitors also have the potential to discriminate between different conformations of a given kinase; thus, small molecules offer a means to dissect the respective functions of those conformations.
Thus, there is an ongoing need for kinase inhibitors and ATPase inhibitors that have improved potency and selectivity. Moreover, the design and synthesis of such inhibitors and of targeted libraries of inhibitors remains challenging; thus, there is an ongoing need for improved synthetic methods.